A novel likely pathogenic germline variant in CDKN1B in a patient with MEN4 and medullary thyroid cancer.

Multiple endocrine neoplasia type 4 (MEN4) is caused by a germline CDKN1B deleterious variant. CDKN1B encodes p27Kip1, a cyclin-dependent kinase inhibitor that acts as tumor-suppressor. Clinical presentation of MEN4 is similar to multiple endocrine neoplasia type 1 (MEN1) but the diagnosis of MEN4 can only be established once a germline CDKN1B pathogenic variant has been confirmed. We describe a unique case presenting with two -rare endocrine conditions. A 59-year-old female patient was diagnosed with medullary thyroid cancer (MTC) without evidence of a germline pathogenic variant in the RET proto-oncogene. Five years later, she developed Cushing's disease. A heterozygous germline variant was identified in the CDKN1B gene, specifically c.536del (p.Prol179GlnfsTer46), corresponding to a single-nucleotide deletion at position 536. This variant induces a frameshift, leading to an alternative stop codon. Immunostaining of the pituitary and thyroid tumors revealed a weak nuclear expression of p27/Kip1 without significant differences of expression between tumor and non-tumoral tissues. The NGS panel (Oncomine Comprehensive Assay v3) performed in both MTC and pituitary tissues identified the germline CDKN1B variant, as well as a pathogenic missense somatic variant c.182 A > G, p.(Gln61Arg) in HRAS in the MTC, without any RET somatic pathogenic variant. Evaluation of loss of heterozygosity (LOH) in both MTC and pituitary tissues showed compatibility with copy-neutral LOH, although further evidence is required for definitive confirmation. In conclusion, we report a clinical case of MTC coexisting with MEN4 due to a novel CDKN1B germline heterozygote frameshift variant.